Effects of a reduction in the number of gap junction channels or in their conductance on ischemia-reperfusion arrhythmias in isolated mouse hearts

Abstract

A transient reduction of cell coupling during reperfusion limits myocardial necrosis, but little is known about its arrhythmogenic effects during ischemia-reperfusion. Thus, we analyzed the effect of an extreme reduction in the number of gap junction channels or in their unitary conductance on ventricular arrhythmias during myocardial ischemia-reperfusion. Available gap junction uncouplers have electrophysiological effects independent from their uncoupling actions. Thus, isolated hearts from Cx43(Cre-ER(T)/fl) mice treated with 4-hydroxytamoxifen (4-OHT), from Cx43KI32 mice [in which connexin (Cx)43 was replaced with Cx32], and from control animals were submitted to regional ischemia and reperfusion, and spontaneous and induced ventricular arrhythmias were monitored. In additional hearts, changes in activation time and electrical impedance during global ischemia-reperfusion were assessed. In contrast to treatment with 4-OHT, replacement of Cx43 with Cx32 did not modify baseline activation time or electrical impedance. However, the number of extrasistole and ventricular tachyarrhythmias was higher in isolated hearts from Cx43KI32 and 4-OHT-treated Cx43(Cre-ER(T)/fl) animals versus wild-type animals during normoxia, ischemia (12.29 ± 3.26 and 52.17 ± 22.51 vs. 3.00 ± 1.46 spontaneous tachyarrhythmias, P < 0.05), and reperfusion. The impairment in conduction during ischemia was steeper in isolated hearts from Cx43KI32 animals, whereas changes in myocardial impedance were attenuated during ischemia in both transgenic models, suggesting altered cell-to-cell coupling at baseline. In conclusion, both reduction of Cx43 with 4-OHT and replacement of Cx43 by less-conductive Cx32 were arrhythmogenic under normoxia and ischemia-reperfusion, despite no major effects on baseline electrical properties. These results suggest that modifications in gap junction communication silent under normal conditions may be arrhythmogenic during ischemia-reperfusion.

Mechanisms Underlying the Emergence of Post-acidosis Arrhythmia at the Tissue Level: A Theoretical Study

“…These findings were supported by a previous study which has suggested an extreme reduction in the number of gap junction channels is arrhythmogenic during ischaemia-reperfusion (Sánchez et al, 2011). On the one hand, the number of contiguous myocytes exhibiting suprathreshold DADs for producing a propagating PVC was significantly reduced in gap junctional uncoupling settings.…”

“…Although it is known that changes in AP and cytoplasmic calcium concentration induced by acidosis may constitute arrhythmogenic substrates for reentry, the evolution of reentry resulted from acidosis-induced electrophysiological changes has not yet been fully characterized. Multiple experimental studies demonstrated that increased cytoplasmic calcium concentration may increase gap junction resistance (Noma and Tsuboi, 1987; Peracchia, 2004), and down-regulation of connexin proteins as well as the presence of severe fibrosis were also observed in ischaemic tissues (de Groot et al, 2001; de Groot and Coronel, 2004; Sánchez et al, 2011; Saffitz and Kleber, 2012). Cell-to-cell uncoupling would be expected to lead to slow propagation of excitation waves (Saffitz and Kleber, 2012).…”

Heptanol decreases the incidence of ischemia-induced ventricular arrhythmias through altering electrophysiological properties and connexin 43 in rat hearts

“…We observed that the expression of Cx43 in the ischemic myocardium was lower compared to that in the normal myocardium, indicating that ischemia may damage gap junctions (18,19). A number of factors may be involved in this change, such as the decrease in the pH and the accumulation of free radicals and lipid metabolites.…”

Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury

“…Thus, Gap26/27 peptides may have targets other than Cx43 hemichannels that confer additional protective potential. Most notably in this context is the fact that Gap19 does not inhibit GJs and thereby circumvents potential pro-arrhythmogenic effects of decreased GJ coupling during ischemia/reperfusion [32, 60]. Obviously, it would be interesting to further substantiate the effects of Gap19 on hemichannels in the in vivo situation; however, single-channel measurements under those conditions are extremely difficult to perform because the large degree of cardiomyocyte coupling via GJs precludes reliable space clamp conditions.…”